CN107496388A - A kind of powderous preparations containing Formoterol and tiotropium salt composition and preparation method thereof - Google Patents
A kind of powderous preparations containing Formoterol and tiotropium salt composition and preparation method thereof Download PDFInfo
- Publication number
- CN107496388A CN107496388A CN201710843836.1A CN201710843836A CN107496388A CN 107496388 A CN107496388 A CN 107496388A CN 201710843836 A CN201710843836 A CN 201710843836A CN 107496388 A CN107496388 A CN 107496388A
- Authority
- CN
- China
- Prior art keywords
- dry powder
- formoterol
- tiotropium
- pharmaceutically acceptable
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Contain Formoterol or its pharmaceutically acceptable salt and tiotropium salt dry powder drug composition and preparation method thereof, and purposes of the dry powder composite in the breathing problems such as treatment asthma, chronic obstructive pulmonary disease for oral inhalation the present invention relates to a kind of.Specifically, Fu Mote or the aerodynamic size of its pharmaceutically acceptable salt and tiotropium salt are not less than 30% less than the percentage by weight of 5 μm of particles in pharmaceutical composition of the present invention, and the two aerodynamic size is less than the ratio of 5 μm of particles 1:In the range of 0.8~1.2, collaboration plays the effect of diastole bronchial smooth muscle.
Description
Technical field
The present invention relates to technical field of medicine, and in particular to a kind of containing Formoterol and tiotropium salt composition
Powderous preparations and preparation method thereof.
Background technology
Formoterol, chemical name are N- [2- hydroxyls -5- (((2- (4- methoxyphenyls) -1- methyl second of 1- hydroxyls -2
Base) amino) ethyl) phenyl] formamide, the form of its fumarate is particularly, is that one kind is used to treat inflammatory or obstructive gas
The bronchodilators of tract disease.
Tiotropium Bromide, chemical name are (1 α, 2 α, 5 α, 7 α) -7- ((- 2- thienyls acetyl group of hydroxyl two) epoxide) -9,9-
The ring (3.3.1.02,4) of dimethyl -3- oxa- -9- nitrogen three-nonane bromide, it is a kind of cholinolytic class medicine of New-type long-acting
(LAMA), contestable selective exclusion M1 and M3 acceptor, and then change vagal tone and play expansion bronchus, alleviate gas
The effect of flow blocked, the contraction of the bronchial smooth muscle of m receptor mediation can be blocked for a long time, the closure of small airway is reduced, enters
And make Airway dilation.
The published pharmacodynamic experiments of CN105125542A prove that Tiotropium Bromide and Formoterol have collaboration summation action,
Generation bronchiectatic activity that can be faster stronger.It has been found that by using Formoterol or its salt or solvate and thiophene support
Ammonium salt, which carries out therapeutic alliance, can obtain unexpected treatment benefit when treating inflammatory or obstructive airway diseases, be particularly
The treatment benefit of collaboration.For example, compared with exclusive use Formoterol or tiotropium salt carry out treatment, can using the conjoint therapy
Dosage needed for given therapeutic effect is reached with obvious reduction, so as to greatly reduce possible adverse side effect.The opposing party
Face, the bronchodilator of combination inhalation difference mechanism of action can strengthen the bronchorelaxing activity of medicine, be effectively improved COPD
The excessive inflation of patient and expiratory dyspnea, and significantly improve every lung function index.There are studies have shown that Tiotropium Bromide and Fu Mote
Tiotropium Bromide, which is used alone, in sieve use in conjunction ratio can significantly improve FEV1, preferably improve expiratory dyspnea symptom, it is anxious to reduce COPD
Property aggravate (AECOPD) number.The conjoint therapy not only works rapidly, and acting duration is grown, so as to which patient can feel
Feel that illness improves rapidly, and because the duration of effect is grown, so as to short-acting anxious effect medicine such as salbutamol or special cloth
He reduces the demand of woods.
WO00/69468 discloses the effective chemical combination of anticholinergic of the beta-mimetics for being related to Formoterol and Tiotropium Bromide
The pharmaceutical composition of thing, preferably metered aerosol (Respimat) form is administered, and can spray decoction under high pressure and be inhaled with producing
Entering property particle.
CN105106200A is disclosed by the way that metered dose inhaler is transpulmonary or nasal delivery there tiotropium salt and Formoterol salt exist
The common suspension formed in suspension media.By sucking the composition, the patient breaths for suffering from PUD D or illness can be made
Capacity (IC) increases at least 350ml.
Due to the need of composition for inhalation are used being related in this area in the therapeutic alliance of above two or multiple actives
Ask growing, there is provided the novel formulation that accurate and different uniform amount inhalable drug is administered simultaneously to patient Yu of customized management
Research and development be highly desirable.
The comparison that combination and its curative effect of this area patent to above-mentioned two classes medicine at present refers to is more, but lacks to how to protect
Demonstrate,prove setting dosage each active delivery to active component key technology research, particularly be adapted to industrialized production pass
The research of key technology.It is as well known to those skilled in the art, in the drug regimen containing two or more active materials for suction
In thing, due to excipient and the interaction of active component and active component to each other, ensure that different activities composition obtains
Effectively delivering is very difficult.
How the formulation and technology of inhalation powder spray is rationally designed so that various active composition, carrier, preparation technology control exist
In certain limit, so as to ensure that each active component of setting dosage reaches active component, synergy is played, compound is inhaled
Enter most important for product.
The content of the invention
The defects of in order to overcome prior art, meet the needs of this area, be used to pass through it is an object of the invention to provide one kind
Mouth inhalation contains Formoterol or the dry powder composite of its pharmaceutically acceptable salt and tiotropium salt medicine, said composition
Accurately and equably by each active delivery of setting dosage to active component both active ingredients can be enable to cooperate with
Play the effect of diastole bronchial smooth muscle.
It is a further object to provide the preparation method of the dry-powder medicament composition.
The present invention further objective is that providing the purposes of the dry-powder medicament composition.
The purpose of the present invention is achieved through the following technical solutions.
The present invention provides a kind of inhalable medicament dry powder composite, by Formoterol or its pharmaceutically acceptable salt,
Tiotropium salt and pharmaceutical acceptable carrier composition, it is characterised in that the air of the Formoterol or its pharmaceutically acceptable salt moves
The mass percent that particle of the mechanics particle diameter less than 5 μm accounts for whole Formoterols or its pharmaceutically acceptable salt is at least
30%, particle of the aerodynamic size less than 5 μm of the tiotropium salt accounts for the mass percent of whole tiotropium salts at least
For 30%, Formoterol or the aerodynamic size of its pharmaceutically acceptable salt and tiotropium salt are less than 5 μm of particle ratio
Example is 1:0.8~1.2.
The suitable pharmaceutically acceptable salt of Formoterol include it is known in the art those, and they are typically derived from
The inorganic acid or organic acid added on medicine.Non-exclusive example includes hydrochloride, hydrobromate, acetate, formates, halogen
Generation and alkylbenzoic acid salt, tartrate, citrate, fumarate, fluoroform sulphonate or salicylate, it is particularly preferably rich
Horse acid Formoterol.
Tiotropium salt includes the salt containing one of cation tiotropium and following anion：Bromide ion, fluorine ion, chlorine from
Son, iodide ion, C1-C4- alkyl sulfates, sulfate radical, bisulfate ion, phosphate radical, hydrogen phosphate, dihydrogen phosphate, nitrate anion,
Maleate, acetate, trifluoroacetic acid root, citrate, fumaric acid radical, tartrate anion, oxalate, amber acid radical and benzoic acid
Root, can optionally through fluorine on alkyl mono-, di- or trisubstituted C1-C4- alkyl azochlorosulfonates, or can be optionally through C1-
C4- alkyl single or multiple substituted phenylbenzimidazole sulfonic acid root on phenyl ring.In these anion, preferred bromide.
Due to the special physiological structure of lung, it is also well known that the active ingredient medicine particle in suction preparation needs small
In 5 μm of site of action of being allowed for access, the aerodynamic diameter of preparation effective active composition is sucked generally between 1~5 μm.
Reducing the common method of particle diameter includes air-flow crushing, speed lapping, ball milling, spray drying, and shooting flow recrystallization etc..
WO2012/106575, WO2014/167023, CN106551909 disclose the spray drying for being related to Formoterol and Tiotropium Bromide
Technique, can improve the dispersiveness of drug particles, so promote delivery performance, can respiratory and stability.However, drug particle is simultaneously
It is not simple the smaller the better, even if being made up of 100% active component less than 5 μm, if the poor fluidity of powder, most of medicine
Thing can be deposited on the non-targeted position such as pars oralis pharyngis, the upper respiratory tract, and the amount that can reach lung may also only have 5~30%, effectively
Deposition deficiency.
WO2011/120779 discloses a kind of method for preparing inhalable powders, after adding magnesium stearate, passes through high shear
Mixing may be such that active component has the coating rate more than 60%, micronised powder is had more preferably mobility.But relative to
Conventional auxiliary material well known in the art, at present magnesium stearate be used for inhalation route security not yet obtain comprehensive assessment.
Particularly when containing two kinds of active components in composition, ensure that each active component of setting dosage reaches effective portion
Position, synergy is played, is more difficult.
The present inventor by repeatedly experimental studies have found that, a diameter of 1~10 μm as the D10 of dry powder composite, D50 is a diameter of
At 30~70 μm, dry powder particles have suitable mobility, and two kinds of active components is deposited on active component in proper proportions.Institute
State D10 diameters, D50 diameters i.e. cumulative particle sizes percentile and respectively reach particle diameter corresponding when 10%, 50%.Wherein D10
Preferably 1~5 μm of diameter, preferably 45~55 μm of D50 diameters.
Judge the deposition ratio in the effective position (i.e. effective dose of the aerodynamic size less than 5 μm) of suction preparation, typically
Minuteness particle dosage is determined by Cascade Impactor, so as to calculate minuteness particle fraction (FPF), i.e. effective dose.
In dry powder composite of the present invention, described pharmaceutical acceptable carrier may be selected from arabinose, glucose, fructose, ribose, sweet
Reveal the one or more in sugar, sucrose, trehalose, lactose, maltose, starch, glucan or mannitol sugar, preferably lactose.
The non-limiting examples of selectable lactose include, SV010, ML001, SV003, Inhalac 120, Inhalac
400, LH200, LH100, preferably using different model lactose combination.
Pharmaceutical acceptable carrier can optionally carry out micronization processes, be micronized to D50 diameters before being mixed with active component
For 30~70 μm.
The inhalable powders mixture quality of the unit dose of dry powder composite of the present invention is 5~30mg.
In dry powder composite of the present invention, Formoterol or its pharmaceutically acceptable salt：Tiotropium salt:Pharmaceutical acceptable carrier
Part by weight be 1：0.5~12.5：300~70000, preferably 1：2.5~7.5：500~50000, more preferably 1：2.5
~4.5：1100~2800.
The preferably oral inhalation of dry powder composite of the present invention, is delivered to lung.
Dry powder composite of the present invention, it is characterised in that the dry powder composite can use gelatine capsule, hydroxypropyl methylcellulose
Cellulose capsule, polyvinyl chloride, laminate layer In Aluminium Foil Packing, it is administered by capsule-type medicinal powder inhaler and blister-type medicinal powder inhaler；It is preferred that
Exist with 1 μ g to 100 μ g active components unit dose, or, dry powder can be included in multiple dose dry powder in the form of reservoir
In suction apparatus.
The preparation method of dry powder composite of the present invention, comprises the following steps,
Step a)：Formoterol or its pharmaceutically acceptable salt, tiotropium salt and pharmaceutical acceptable carrier with less than 100 turns/
The mixed on low speed of minute, obtain the good mixture of mixture homogeneity；
Step b)：The mixture with 100 revs/min~4000 revs/min of mixed at high speed, preferably 500 revs/min~
3000 revs/min of mixed at high speed, more preferably with 600 revs/min~1500 revs/min of mixed at high speed.
The mixed method is in the methods of sieving mixing, V-arrangement mixing, three-dimensional hybrid, shear-mixed, mechanical fusion
It is one or more of.
The time of wherein mixed on low speed is unrestricted, time of mixed at high speed should not it is long be common sense in the field, it is proposed that control
System was at 10 minutes or so.
In above-mentioned steps a), b) before, active component can be pre-processed, the pretreatment is by Formoterol and thiophene
Support ammonium salt passes through the one or more in air-flow crushing, speed lapping, ball milling, spray drying, and shooting flow recrystallization
Method reduces a diameter of 1~10 μm, preferably 1.5~5.5 μm of particle diameter, the Formoterol of preparation and the D50 of tiotropium.
Optionally, precomminution optionally can be carried out to pharmaceutically acceptable auxiliaries, makes a diameter of 30~70 μm of its D50.
Optionally, sieving processing can be carried out to active component and pharmaceutically acceptable auxiliaries before combination.
The present invention also provides described dry powder composite and prepared for treating asthma, chronic obstructive pulmonary disease (COPD) etc.
Purposes in the medicine of breathing problem.
Beneficial effects of the present invention are：
The inhalable powder mixture that the present invention prepares, the aerodynamic size of two of which active component are less than
The percentage by weight of 5 μm of particles is at least respectively 30%, and the ratio that the two aerodynamic size is less than 5 μm of particles is 1:0.8
~1.2, it can ensure that each active component of setting dosage reaches active component, can farthest play the collaboration of drug regimen
The breathing problem such as curative effect, treatment asthma, chronic obstructive pulmonary disease (COPD) works well.
Formulation and technology of the present invention is simple, easy to operate, is particularly suitable for industrialized production.
(fluticasone propionate, Si Lihua, letter must can between 15~20% by the FPF of most classical inhalation powder spray in the market
All treasured etc.), effective precipitation is relatively low.The present invention has reached effects of the more preferable FPF more than 30% using simple technique.
Brief description of the drawings
Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein：
Fig. 1：Particle diameter distribution before Tiotropium Bromide-micronizing
Fig. 2：Particle diameter distribution after Tiotropium Bromide-micronizing
Fig. 3：Particle diameter distribution before formoterol fumarate-micronizing
Fig. 4：Particle diameter distribution after formoterol fumarate-micronizing
Fig. 5:The particle diameter distribution of prescription 1
Fig. 6：The particle diameter distribution of prescription 2
Fig. 7：The particle diameter distribution of prescription 3
Fig. 8：The particle diameter distribution of prescription 4
Fig. 9：The particle diameter distribution of prescription 9
Figure 10：The particle diameter distribution of prescription 10
Figure 11：The particle diameter distribution of prescription 11
Figure 12：The particle diameter distribution of prescription 12
Figure 13：The particle diameter distribution of prescription 13
Embodiment
The present invention is further described in detail with reference to specific embodiment, the embodiment provided is only for illustrating
The present invention, the scope being not intended to be limiting of the invention.
The experimental method of unreceipted actual conditions in following embodiments, generally according to normal condition or according to institute of manufacturer
It is recommended that condition.Unless otherwise defined, all specialties used in text are familiar with scientific words with one skilled in the art
Meaning it is identical.
In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Text
Described in preferable implementation only present a demonstration and be used with material.
SV010 in following embodiments, ML001, SV003, Inhalac 120, Inhalac 400, LH200, LH100,
It is suction lactose model.
Carrier in following embodiments optionally conventional method can be used to carry out precomminution processing.
Embodiment 1：Tiotropium Bromide is micronized
Using TECNOLOGIA MECCANICA J-20 airslide disintegrating mills, setting crushes pressure and feed pressure is respectively
1.2Mpa and 1.0Mpa, feed intake and carry out air-flow crushing.
Embodiment 2：Formoterol fumarate is micronized
Using the ball mills of Retsch MM 200, frequency 25Hz is set, feeds intake and carries out dry ball milling.
Embodiment 3：Particle size determination before and after Tiotropium Bromide, formoterol fumarate micronizing
Determine Tiotropium Bromide in Examples 1 and 2, the particle diameter before and after formoterol fumarate micronizing.
Particle diameter is determined using SYMPATEC.Operation is as follows：
1st, the HELOS (H2969) and RODOS that installs instruments is operated
2nd, flow velocity is adjusted to 4.0bar
3rd, software is opened, measuring environment value, sample is filled, starts to measure；It is repeated 2 times.
Wherein, particle diameter distribution the results are shown in Table 1, Fig. 1~2 before and after Tiotropium Bromide micronizing；Formoterol fumarate is micronized
Front and rear particle diameter distribution the results are shown in Table 2, Fig. 3~4.
Particle diameter distribution before and after the micronizing of the Tiotropium Bromide of table 1.
Particle diameter distribution before and after the micronizing of the formoterol fumarate of table 2.
Embodiment 4：Prescription 1
Tiotropium Bromide, formoterol fumarate and carrier after being micronized according to embodiment 1,2 are crossed into 40 mesh sieves respectively.By gained
Pre-composition three-dimensional hybrid (T2F) 5min, rotating speed 72rpm；10min is mixed through high-speed stirred (G6) again, rotating speed 600rpm, produces dry powder.
Intermediate quantitative filling often inhales 25mg in gelatine capsule.
Embodiment 5：Prescription 2
Tiotropium Bromide, formoterol fumarate and carrier after being micronized according to embodiment 1,2 are crossed into 40 mesh sieves respectively.Will
Gained pre-composition V-type mixes (KCH-10) 30min, rotating speed 50rpm；Again 10min, rotating speed are mixed through high-speed stirred (G6)
300rpm, produce dry powder.
Intermediate quantitative filling often inhales 20mg in hypromellose cellulose capsule.
Embodiment 6：Prescription 3
By Tiotropium Bromide, formoterol fumarate and carrier three-dimensional hybrid (T2F) after being micronized according to embodiment 1,2
10min, rotating speed 10rpm；10min is mixed through high-speed stirred (G6) again, rotating speed 1000rpm, produces dry powder.
Intermediate quantitative filling often inhales 30mg in gelatine capsule.
Embodiment 7：Prescription 4
Tiotropium Bromide, formoterol fumarate and carrier equal increments after being micronized according to embodiment 1,2 are crossed into 30 mesh
Sieve.Gained pre-composition V-type is mixed into (KCH-10) 20min, rotating speed 30rpm；Again through mechanical fusion (Picomix, HOSOKAWA)
8min is mixed, rotating speed 1500rpm, produces dry powder.
Intermediate quantitative filling often inhales 5mg in polyvinyl chloride bubble-cap.
Embodiment 8：Prescription 5
Tiotropium Bromide 22.5mg
Formoterol fumarate 9mg
Mannitol 25.0g
Tiotropium Bromide after being micronized according to embodiment 1,2, formoterol fumarate, carrier are crossed into 40 mesh sieves respectively.Will
Gained pre-composition three-dimensional hybrid (T2F) 5min, rotating speed 72rpm；10min, rotating speed 4000rpm are mixed through high-speed stirred (G6) again,
Produce dry powder.
Intermediate quantitative filling often inhales 25mg in gelatine capsule.
Embodiment 9：Prescription 6
Tiotropium Bromide 22.5mg
Formoterol fumarate 9mg
Glucose 25.0g
Tiotropium Bromide, formoterol fumarate and carrier after being micronized according to embodiment 1,2 are crossed into 40 mesh sieves respectively.Will
Gained pre-composition three-dimensional hybrid (T2F) 5min, rotating speed 100rpm；10min, rotating speed 500rpm are mixed through high-speed stirred (G6) again,
Produce dry powder.
Intermediate quantitative filling often inhales 25mg in gelatine capsule.
Embodiment 10：Prescription 7
Tiotropium Bromide 40.5mg
Formoterol fumarate 9mg
Leucine 25.0g
Tiotropium Bromide, formoterol fumarate and carrier after being micronized according to embodiment 1,2 are crossed into 40 mesh sieves respectively.Will
Gained pre-composition three-dimensional hybrid (T2F) 5min, rotating speed 72rpm；10min, rotating speed 3000rpm are mixed through high-speed stirred (G6) again,
Produce dry powder.
Intermediate quantitative filling often inhales 25mg in gelatine capsule.
Embodiment 11：Prescription 8
Tiotropium Bromide 22.5mg
Formoterol fumarate 9mg
Starch 25.0g
Tiotropium Bromide, formoterol fumarate and carrier after being micronized according to embodiment 1,2 are crossed into 40 mesh sieves respectively.Will
Gained pre-composition three-dimensional hybrid (T2F) 5min, rotating speed 72rpm；10min, rotating speed 600rpm are mixed through high-speed stirred (G6) again, i.e.,
Obtain dry powder.
Intermediate quantitative filling often inhales 25mg in gelatine capsule.
Comparative example 1：Prescription 9
By according to the Tiotropium Bromide after embodiment 1,2 micro mists, formoterol fumarate and carrier mechanical fusion (Picomix,
HOSOKAWA 8min) is mixed, rotating speed 2500rpm, produces dry powder.
By intermediate quantitative filling in gelatine capsule, 20mg is often inhaled.
Comparative example 2：Prescription 10
By Tiotropium Bromide, formoterol fumarate and carrier three-dimensional hybrid (T2F) after being micronized according to embodiment 1,2
8min, rotating speed 56rpm, produces dry powder.By intermediate quantitative filling in gelatine capsule, 20mg is often inhaled.
Comparative example 3：Prescription 11
Tiotropium Bromide 22.5mg
Formoterol fumarate 9mg
LH100 24.0g
Wherein carrier is not crushed to 30~70 μm of D50 before combination.
Tiotropium Bromide, formoterol fumarate and carrier equal increments after being micronized according to embodiment 1,2 are crossed into 30 mesh
Sieve.Gained pre-composition V-type is mixed into (KCH-10) 20min, rotating speed 50rpm；Again through mechanical fusion (Picomix, HOSOKAWA)
8min is mixed, rotating speed 1200rpm, produces dry powder.
Intermediate quantitative filling often inhales 5mg in polyvinyl chloride bubble-cap.
Comparative example 4：Prescription 12
Wherein carrier is not crushed to 30~70 μm of D50 before combination.
Tiotropium Bromide, formoterol fumarate and carrier equal increments after being micronized according to embodiment 1,2 are crossed into 30 mesh
Sieve.Gained pre-composition V-type is mixed into (KCH-10) 20min, rotating speed 50rpm；Again through mechanical fusion (Picomix, HOSOKAWA)
8min is mixed, rotating speed 1200rpm, produces dry powder.
Intermediate quantitative filling often inhales 5mg in polyvinyl chloride bubble-cap.
Embodiment 12：Prescription 13, industrialized production (100,000/batches)
Tiotropium Bromide, formoterol fumarate and carrier after being micronized according to embodiment 1,2 are crossed into 40 mesh sieves respectively.Will
Gained pre-composition three-dimensional hybrid (T2F) 5min, rotating speed 72rpm；10min, rotating speed 600rpm are mixed through high-speed stirred (G10) again,
Produce dry powder.
Powder to be filled is fitted into 3# hydroxypropyl methylcellulose Capsuleses with ModuC-LS capsule fillers, often inhaled
25mg。
The capsule filled carries out aluminium-aluminium and packed, and after air pressure >=0.6MPa to be compressed, is grasped according to corresponding operating code
Make, start aluminium aluminium machine, set heat-sealing temperature as 180 ± 10 DEG C, regulation 20~40 beats/min of speed of punching.Double aluminium sheets are with totally
Container contain.
Embodiment 13：The particle diameter of dry powder composite
Using new pa Tyke laser particle analyzer (RODOS) measure prescription 1~4, the particle diameter of prescription 9~13.Operation is as follows.
1st, the HELOS (H2969) and RODOS that installs instruments is operated
2nd, flow velocity is adjusted to 4.0bar
3rd, software is opened, measuring environment value, sample is filled, starts to measure；It is repeated 2 times.
As a result such as table 3 and Fig. 5~13.
The particle diameter distribution (n=2) of the prescription 1~4,9~13 of table 3.
Measurement result shows that the D10 of prescription 11 is more than 10 μm, and D50 is more than 70 μm；The D50 diameters of prescription 12 are less than 30 μm.
Embodiment 14：1~13 external performance measurement of prescription
According to 2010 editions annex X H droplets (grain) determination methods (twin stage impinger determination method) of Chinese Pharmacopoeia respectively to prescription 1
~13 carry out minuteness particle dosimetry, and so as to calculate minuteness particle dosage (FPF), operation is as follows：
1. install instruments TI, reception liquid (I grade of addition 7ml solvent, II grade adds 30ml solvents) is added；
2. flow velocity is adjusted to 60 ± 2L/min；
3. powder charge, vertically puncturing capsule, throat is inserted；
4. opening three-phase valve, 10s is evacuated；
5. close three-phase valve；
6. repeating said process completes 10 capsule measure
Measurement result is shown in Table 4..
The FPF results of the prescription 1~13 of table 4. collect
The result explanation of comparative example prescription 9~10：Only with high-speed stirred or stirring at low speed technique, two kinds of active components has
Effect site deposition rate difference significantly increases；Therefore need to select suitable hybrid technique, compound product is reached ideal and pass
Send performance.
Prescription 1~4 and comparative example prescription 11~12 comparing result explanation of the present invention, composition (the i.e. kind of lactose carrier
Class and proportioning) deposition ratio in the effective position of active component can be significantly affected.D50 and D10 is excessive or too small so that active component
Deposition reduces.Therefore rational prescription proportioning, the mobility and delivery performance of prescription powder are determined.
The result of prescription 13 shows that formulation and technology of the present invention is amplified to 100,000 scales, prescription stable performance, suitable for industry
Metaplasia is produced.
Claims (10)
1. a kind of inhalable medicament dry powder composite, by Formoterol or its pharmaceutically acceptable salt, tiotropium salt and can
Pharmaceutical carrier forms, it is characterised in that the aerodynamic size of the Formoterol or its pharmaceutically acceptable salt is less than 5
μm particle account for the mass percents of whole Formoterols or its pharmaceutically acceptable salt and be at least 30%, the tiotropium salt
Aerodynamic size the mass percents of whole tiotropium salts accounted for less than 5 μm of particle be at least 30%, Formoterol or
Particle ratio of the aerodynamic size of its pharmaceutically acceptable salt and tiotropium salt less than 5 μm is 1:0.8~1.2.
2. dry powder composite according to claim 1, it is characterised in that the D10 a diameter of 1 of the dry powder composite~
10 μm, preferably 1~5 μm, a diameter of 30~70 μm, preferably 45~55 μm of D50.
3. dry powder composite according to claim 1 or 2, wherein described pharmaceutical acceptable carrier be selected from arabinose, glucose,
One or more in fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starch, glucan or mannitol sugar,
It is preferred that the combination of the lactose of lactose, more preferably different model.
4. according to the dry powder composite described in claim any one of 1-3, it is characterised in that the inhalable powders of unit dose are mixed
Compound quality is 5~30mg, wherein Formoterol or its pharmaceutically acceptable salt：Tiotropium salt:The weight of pharmaceutical acceptable carrier
Ratio is 1：0.5~12.5：300~70000, preferably 1：2.5~7.5：500~50000.
5. according to the dry powder composite described in claim any one of 1-4, the Formoterol or its pharmaceutically acceptable salt
Selected from formoterol fumarate, the tiotropium salt is selected from Tiotropium Bromide.
6. according to the dry powder composite described in claim any one of 1-5, it is characterised in that the dry powder composite can be with bright
Glue capsule, HPMC capsule, polyvinyl chloride, laminate layer In Aluminium Foil Packing, pass through capsule-type medicinal powder inhaler and blister-type
Medicinal powder inhaler is administered；It is preferred that exist with 1 μ g to 100 μ g active components unit dose, or, dry powder can be with the shape of reservoir
Formula is included in multiple dose powder inhaler；It is preferred that oral inhalation, is delivered to lung.
A kind of 7. preparation method of the dry powder composite described in any one of claim 1-6, it is characterised in that comprise the following steps,
Step a)：Formoterol or its pharmaceutically acceptable salt, tiotropium salt and pharmaceutical acceptable carrier are with less than 100 revs/min
Mixed on low speed, obtain the good mixture of mixture homogeneity；
Step b)：The mixture is with 100 revs/min~4000 revs/min of mixed at high speed；It is preferred that 500 revs/min~3000
Rev/min mixed at high speed.
8. preparation method according to claim 7, wherein the mixing selected from sieving mixing, V-arrangement mixing, three-dimensional hybrid,
One or more in the methods of shear-mixed, mechanical fusion.
9. the preparation method according to claim 7 or 8, it is characterised in that pre-processed to active component, the pre- place
Manage as Formoterol and tiotropium salt are passed through into air-flow crushing, speed lapping, ball milling, spray drying, and shooting flow body weight
One or more of methods in crystallization reduce particle diameter, the Formoterol of preparation and a diameter of 1~10 μm of the D50 of tiotropium, preferably
1.5~5.5 μm；Optionally, precomminution is carried out to pharmaceutically acceptable auxiliaries, makes a diameter of 30~70 μm of its D50.
10. the dry powder composite described in a kind of claim 1-6 is being prepared for treating asthma, chronic obstructive pulmonary disease (COPD)
Etc. the purposes in the medicine of breathing problem.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710843836.1A CN107496388B (en) | 2017-09-19 | 2017-09-19 | Powdery preparation containing formoterol and tiotropium salt composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710843836.1A CN107496388B (en) | 2017-09-19 | 2017-09-19 | Powdery preparation containing formoterol and tiotropium salt composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107496388A true CN107496388A (en) | 2017-12-22 |
| CN107496388B CN107496388B (en) | 2020-12-15 |
Family
ID=60697747
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710843836.1A Active CN107496388B (en) | 2017-09-19 | 2017-09-19 | Powdery preparation containing formoterol and tiotropium salt composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107496388B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109745565A (en) * | 2019-01-28 | 2019-05-14 | 上海方予健康医药科技有限公司 | A kind of dry powder composite and preparation method thereof for sucking |
| CN109745564A (en) * | 2019-01-28 | 2019-05-14 | 上海方予健康医药科技有限公司 | A kind of preparation method sucking dry powder composite |
| CN111297837A (en) * | 2020-03-26 | 2020-06-19 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756942A (en) * | 2008-12-25 | 2010-06-30 | 天津金耀集团有限公司 | Oral lung inhalation aerosol powder |
| CN105125542A (en) * | 2015-08-23 | 2015-12-09 | 杭州紫金医药科技有限公司 | Medicine composition with tiotropium bromide and formoterol, application of medicine composition and preparation |
-
2017
- 2017-09-19 CN CN201710843836.1A patent/CN107496388B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756942A (en) * | 2008-12-25 | 2010-06-30 | 天津金耀集团有限公司 | Oral lung inhalation aerosol powder |
| CN105125542A (en) * | 2015-08-23 | 2015-12-09 | 杭州紫金医药科技有限公司 | Medicine composition with tiotropium bromide and formoterol, application of medicine composition and preparation |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109745565A (en) * | 2019-01-28 | 2019-05-14 | 上海方予健康医药科技有限公司 | A kind of dry powder composite and preparation method thereof for sucking |
| CN109745564A (en) * | 2019-01-28 | 2019-05-14 | 上海方予健康医药科技有限公司 | A kind of preparation method sucking dry powder composite |
| CN109745565B (en) * | 2019-01-28 | 2021-05-18 | 上海方予健康医药科技有限公司 | Dry powder composition for inhalation and preparation method thereof |
| CN111297837A (en) * | 2020-03-26 | 2020-06-19 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
| CN111297837B (en) * | 2020-03-26 | 2022-02-22 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107496388B (en) | 2020-12-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2749231C (en) | Pharmaceutical composition for inhalation | |
| AU2016262698B2 (en) | Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist | |
| US20060292083A1 (en) | Inhalation compositions with high drug ratios | |
| ZA200502177B (en) | Inhalation composition | |
| CN107496388A (en) | A kind of powderous preparations containing Formoterol and tiotropium salt composition and preparation method thereof | |
| US9987229B2 (en) | Process for preparing a medicament | |
| ZA200502172B (en) | Inhalation compositions with high drug ratios | |
| WO2012168160A1 (en) | Dry powder inhaler compositions comprising umeclidinium | |
| US8273331B2 (en) | Inhalation compositions | |
| WO2019060604A1 (en) | Inhalable medicament | |
| WO2022045995A1 (en) | A process for the preparation of dry powder compositions for inhalation | |
| TW201618759A (en) | Dry powder for inhalation formulation having improved stability of combined active ingredients |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |